Received: October 20, 2015 Accepted: October 20, 2016 Publised online: February 28, 2017Corresponding Author : Mi Young Han, MD, PhDDepartment of Pediatrics, Kyung Hee University School of Medicine, 23 Kyungheedae-ro, Dongdae-mun-gu, Seoul 02447, Korea Tel +82-2-958-8283, Fax +82-2-958-8299E-mail: [email protected]
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Mycoplasma Infection as a Cause of Persistent Fever after Intravenous Immunoglobulin Treatment of Patients with Kawasaki Disease: Frequency and Clinical ImpactHye Rim Park1, Mi Young Han2, Kyung Lim Yoon2, Sung-Ho Cha1, Sung Kyoung Moon3, and Hae Woon Jung1
1Department of Pediatrics, Kyung Hee University Hospital; 2Department of Pediatrics, 3Department of Diagnostic Radiology, Kyung Hee University School of Medicine, Seoul, Korea
Background: Mycoplasma is a common cause of respiratory infections and may require differential diagnosis from Kawasaki disease (KD). In this study, we investigated the frequency and clinical manifestations of mycoplasma infection in patients with KD.Materials and Methods: Medical records of 375 in-patients admitted for treatment during the acute stage of KD, were collected, and reviewed retrospectively. Of these patients, 152 (40.5%) were also tested for recent mycoplasma infection. Patients with positive results (anti-mycoplasma IgM Ab >1:640 or cold agglutinin >1:64) were designated as the case group (n = 37, 24.3%) whereas those with negative results were designated as the control group (n = 115, 75.7%). Clinical findings of the two groups were compared.Results: Patients in the case group were older than those in the control group (mean age, 48.2 ± 32.1 months, vs. 31.7 ± 21.7 months; P = 0.001). There were significant differences between the case and control groups in the changes in the extremities (78.3% vs. 57.4%, respectively; P = 0.031), and in fever duration (6.5 ± 2.5 days vs. 5.4 ± 1.5 days; P = 0.047). Of the 37 pa-tients with positive mycoplasma testing, 7 (18.9%) had persistent fever even after the symptoms and signs of systemic inflamma-tion (acute phase of KD) had been resolved. These patients were positive for mycoplasma infection during further evaluation of persistent fever, and all of them responded to macrolide antibiotics.Conclusions: We found that mycoplasma infection is somewhat related to KD. When fever persists after resolution of the acute stage of KD, mycoplasma infection may be considered as a possible cause of fever in preschool-aged children.
Kawasaki disease (KD) is a main cause of acquired heart dis-
ease in children. At present, the exact etiology of the disease is
unknown. The most plausible hypothesis of KD is systemic
vasculitis in a genetically susceptible individual, due to an
overwhelming immune response triggered by ubiquitous in-
fectious agents. Several studies have attempted to examine the
correlation between some respiratory viruses and KD [1, 2].
In KD patients, respiratory symptoms such as cough (69%),
and rhinorrhea (58%) [3] are often observed.
Mycoplasma infection, contributes to the high incidence of
pneumonia or bronchitis, mainly in school-aged children.
However, younger children are now affected by mycoplasma
infection in Korea due to earlier exposures with daycare atten-
dance at a younger age. The symptoms of extrapulmonary my-
coplasma infection in children are nonspecific and it can hard-
ly be diagnosed on the basis of clinical symptoms and signs [4].
These symptoms are similar or identical to those of KD; there-
fore, Mycoplasma pneumoniae may be one of the infectious
agents that trigger the immune response in KD. In this study,
we evaluated the incidence of recent mycoplasma infection
and its impact on the clinical course and manifestations of KD.
Materials and Methods
Medical records of 375 inpatients admitted in a single center
(Kyung Hee University Hospital, Seoul, Korea) who were treat-
ed for acute stage of KD from January 2000 to December 2013
were retrospectively reviewed.
The Diagnostic Guidelines for KD (American Heart Associa-
tion [AHA], 2004) were used as a reference for the diagnostic
criteria of KD [5].
Each patient was treated initially with 2 g/kg intravenous im-
munoglobulin (IVIG) [5]. Symptoms and signs were observed
for 36 to 48 h after termination of IVIG infusion. Additional
IVIG, steroid (especially intravenous methylprednisolone), or
infliximab was administered when patients were not respon-
sive to the initial IVIG infusion.
After treatment, all KD patients were followed-up with regu-
lar two-dimensional (2D) cardiac echocardiography for one
year. Abnormalities of coronary arteries were diagnosed by 2D
echocardiography, according to the 2004 AHA guidelines [5].
Among 375 patients, 152 (40.5%) patients were also tested
for mycoplasma infections by enzyme immunoassay (Sero-
dia-Myco II, Fujirebio, Japan, from 2011). The patients were
classified into two groups: 37 (24.3%) with positive results (case
group) and 115 (75.7%) with negative results (control group). A
positive result was defined as the presence of anti-mycoplas-
ma IgM ≥1:640 or an increase in anti-mycoplasma IgG by more
than 4-fold in consecutive tests between 10 to 21 days [6]. As
anti-mycoplasma IgM can remain positive for up to 6 to 12
months after infection, the positive group includes acute and
recent infections.
Clinical profiles of the two groups were compared. All labo-
ratory data were collected before IVIG was started. Clinical
manifestations, respiratory symptoms, and chest X-rays of the
patients with persistent fever after treatment were analyzed.
Positive respiratory symptoms were defined as one or more
of the following on admission: cough, sputum, or rhinorrhea.
All statistical analyses were performed using SPSS version
22.0 for Windows (IBM, Chicago, IL, USA). P values of <0.05
were considered as statistically significant. Data were present-
ed as mean ± standard deviation. Continuous numeric vari-
ables were analyzed by Student t-test, and categorical variables
were analyzed by Pearson Chi-square test or Fisher’s exact test.
Results
1. Mycoplasma testing of Kawasaki disease patients
The numbers of KD patients admitted each year from 2000
to 2013, patients chosen from mycoplasma testing and those
positive for mycoplasma infection are shown in Figure 1. From
2000 to 2005, KD patients were rarely tested for anti-mycoplas-
ma antibody or cold agglutinin. In 2006 to 2007 and 2011, there
Figure 1. Distribution of Kawasaki disease patients who underwent test-ing for mycoplasma and those who tested positive for mycoplasma (January 1, 2000 – December 31, 2013). Myco, Mycoplasma pneumonia; KD, Kawasaki disease.
Park HR, et al. • Mycoplasma infection in Kawasaki disease www.icjournal.org40
were nationwide mycoplasma epidemics. Thus, in 2012 and
2013, almost all KD patients had anti-mycoplasma antibody
testing as part of the initial laboratory tests.
2. Clinical manifestations
Clinical manifestations of the patients are compared in Table 1.
There were statistically significant differences between the case
and control groups in the changes in the extremities, including
erythematous changes and/or edema of the hands and feet
(78.3% vs. 57.4%, respectively; P = 0.031), the duration of fever
(6.5 ± 2.5 days vs. 5.4 ± 1.5 days; P = 0.047), and in the mean age
of KD onset (48.2 ± 32.1 months vs. 31.7 ± 21.7 months; P =
0.001).
The case and control groups did not differ significantly in
gender (P = 0.314), and in other clinical criteria of KD, such as
presence or absence of bilateral conjunctival injection (94.6%
vs. 90.4%; P = 0.431), mucosal changes (91.9% vs. 85.2%; P =
0.406), polymorphous rash (89.2% vs. 86.0%; P = 0.783), and
cervical lymphadenopathy (70.2% vs. 61.7%, P = 0.348). No dif-
ferences between the two groups were found in the presence
of incomplete KD (P =0.437), respiratory symptoms (P = 0.476),
response to IVIG (P = 0.951), and development of coronary ar-
tery lesions (P = 0.937).
3. Laboratory data
No significant differences between the case and control
groups were found in laboratory values (hemoglobin [Hb],
white blood cell [WBC] count, C-reactive protein [CRP], aspar-
tate transaminase [AST], alanine transaminase [ALT], and
pyuria; Table 2), and pro-brain natriuretic peptide (proBNP)
concentration (Table 3).
4. Patients with persistent fever after resolution of acute-
stage KD
In 7 (18.9%) patients from the case group, despite an im-
provement in symptoms of acute-stage KD and desquamation
of the extremities after the first or second IVIG treatment, fever
persisted for an additional 48 to 165 hours after the completion
of IVIG infusion. Their clinical characteristics are listed in Ta-
ble 4. Among these 7 patients, 2 had respiratory symptoms on
the first day of admission, 4 patients had chest X-rays consis-
tent with pneumonia and 2 had coronary artery lesions on
echocardiography. Five patients had a secondary IVIG infu-
sion of 2 g/kg; and neither corticosteroid nor infliximab were
used for secondary treatment of acute-stage KD.
Table 1. Clinical characteristics of the mycoplasma positive group (case group) and negative group (control group)
VariablesCase
group (n = 37)
Control group
(n = 115)P-value
Age (months) (range) 48.2 ± 32.1 31.7 ± 21.7 0.001a
Fever duration (day) (range)
6.5 ± 2.5 5.4 ± 1.5 0.047a
Sex (M) (n, %) 25 (67.6) 67 (58.3) 0.314
Clinical criteria (n, %)
Bilateral conjunctival injection
35 (94.6) 104 (90.4) 0.431
Mucosal changes 34 (91.9) 98 (85.2) 0.406
Polymorphous rash 33 (89.2) 99 (86.0) 0.783
Change in the extremi-ties
29 (78.3) 66 (57.4) 0.031a
Cervical lymphadenopa-thy
26 (70.2) 71 (61.7) 0.348
Incomplete KD presenta-tion (n, %)
5 (13.5) 22 (19.1) 0.437
Respiratory symptoms (n, %)
13 (35.1) 48 (41.7) 0.476
Initial IVIG resistance (n, %)
5 (13.5) 16 (14.0) 0.951
Coronary artery lesions (n, %)
5 (14.0) 16 (14.0) 0.937
Values shown marked with aP <0.05.KD, Kawasaki disease; IVIG, intravenous immunoglobulin.
Table 2. Laboratory values in the case and control groups
Mean values, percentages, and standard deviations are shown.WBC, white blood cells; CRP, C-reactive protein; AST, aspartate aminotransferase; ALT, alanine aminotransferase; HPF, high power field.
Table 3. Concentration of pro-brain natriuretic peptide (proBNP) on ad-mission in patients from the case and control groups
Of the 375 KD patients assessed during the study, 152 pa-
tients were tested for mycoplasma, and 37 patients had posi-
tive results. Before 2007, the patients were tested for mycoplas-
ma infection in the presence of cough, rhinorrhea or persistent
fever. From 2007, when there was a mycoplasma epidemic
most patients admitted for KD were initially tested for myco-
plasma infections. The group with positive tests had longer fe-
ver duration, older age, and more changes in the extremities.
Seven (18.9%) patients in the case group had persistent fever
even after resolution of the acute stage of KD.
The mean age of KD patients is generally considered to be 3
years; all patients are younger than 5 years [7]. However, in one
study, the age distribution was 9 to 11 months [3]. Because my-
coplasma infection was common in preschool-aged children
in our study, the onset age of KD may be slightly higher than in
other studies. On the other hand, the youngest mycoplas-
ma-positive child with KD in our study was 2 months of age.
Mycoplasma infection in Korea is not limited to school-aged
children because many infants and younger children are cared
for in daycare centers. Therefore, differential diagnosis between
KD and mycoplasma infection is becoming more important in
Korea. According to our study, recent mycoplasma infection
and KD co-occur more often in older children. Immune modu-
lation of M. pneumoniae infection may results in cross-reac-
tion between bacterial and human cell components, and auto-
immunity may contribute to the pathogenesis of KD [8].
In our study, the mean fever duration was 6.5 days in the my-
coplasma-positive group and 5.4 days, in the negative group. In
general, fever duration in patients with KD is more than 5 days;
it can persist to 14 days when mycoplasma infection present
[9]. Mycoplasma infection alone has a longer fever duration
than KD has. In a study by Lee et al. [8], the mean fever dura-
tion was 9.2 days in the mycoplasma-positive group and 6.9
days in the negative group, which was longer than both groups
in our study.
In our study, changes in the extremities differed significantly
between the mycoplasma-positive and negative groups. The
detailed mechanism of the changes of the extremities in the
acute stage of KD and the following subacute stage is not well
understood. Hand and foot changes in patients with myco-
plasma infection have been described in a case report by Gre-
co et al., 2007 [10]. Although the pathogenesis of the changes
has not been fully elucidated, they may be explained by hyper-
sensitivity vasculitis. The patient reported by Greco et al. had
extrapulmonary symptoms of M. pneumoniae infection,
namely cutaneous vasculitis, as well as inflammation and ne-
crosis of small blood vessel walls.
Of the 37 case group patients, 7 patients had persistent fever
Table 4. Clinical profiles of children with persistent fever after IVIG who were proved to be mycoplasma-positive (n = 7)
No. Sex/age
Fever duration after first IVIG (h)
2nd IVIG
Respiratory symptoms on
admissionChest X-ray reading CAL Antibiotics
Time to start antibiotics after
first IVIG finished (h)
Fever subsided after antibiotics
started (h)
1 M/23 m 57 N Y BLL pneumonia N AZM 50 482 F/5 Y 158 Y N RLL pneumonia N AZM 72 1403 F/7 Y 48 Y N Unremarkable N CLR 24 244 M/5 Y 165 Y N Unremarkable N AZM 162 965 M/4 Y 120 N Y RLF pneumonia Y AZM 168 126 F/5 Y 48 Y N RLF pneumonia N CLR 30 144
7 M/14 m 48 Y N unremarkable Y CLR 72 24
IVIG, intravenous immunoglobulin; CAL, coronary artery lesions; BLL, both lung field; AZM, azithromycin; RLL, right lower lung field; RLF, right lung field; CLR, clarithromy-cin.
Figure 2. Clinical course of case No. 4 (see Table 3).IVIG, intravenous immunoglobulin; HD, hospital day; BT, body temperature; CRP, c-reactive protein.
Park HR, et al. • Mycoplasma infection in Kawasaki disease www.icjournal.org42
after the resolution of acute symptoms and laboratory abnor-
malities. They were reevaluated to identify the cause of sus-
tained fever after use of IVIG. Laboratory studies including
WBC, Hb, Hct, CRP, AST, ALT and immunology assay were
within normal level. Respiratory viral polymerase chain reac-
tion (PCR) was not available for the group. Clarithromycin
(CLR), or azithromycin (AZM) was given to the patients with
subsequent subsiding of fever.
One of these 7 cases (case 4) is described in Figure 2. A
5-year-old male presented with all symptoms of acute-stage
KD and we started treatment with IVIG on the first hospital
day. Almost 48 hours after the end of the first IVIG treatment,
fever and erythema of the hands and feet remained. The pa-
tient was regarded as having refractory acute stage of KD and
the second IVIG treatment was infused on day 4. On day 8,
desquamation of hands and feet was observed yet fever per-
sisted. During evaluation for the sustained fever, CRP was de-
creased and other laboratory findings were normalized, how-
ever anti-mycoplasma IgM titer remained high (>1:1,280) until
day 10. Azithromycin was administered and fever subsided on
day 14. Initially, the child had no respiratory symptoms and
showed unremarkable chest X-ray findings. A follow-up chest
X-ray was also unremarkable. Therefore, mycoplasma infec-
tion may be a cause of persistent fever after the resolution of
acute-stage KD.
In our study, 11 (29.7%) of the 37 case group patients were
treated with macrolide antibiotics. Antibiotics were not used
in the other patients.
Mycoplasma is known as a main cause of pneumonia in
school-aged children. Our results seem to indicate high inci-
dence of recent mycoplasma infection in preschool-aged chil-
dren. Mycoplasma infection has many extrapulmonary symp-
toms such as arthritis, hemolytic anemia and other systemic
symptoms [11]. Symptoms of mycoplasma infection may be
similar to those of KD and concomitant infection with myco-
plasma in KD patients is also possible. Therefore, it is import-
ant to distinguish recent mycoplasma infection from KD in pa-
tients with fever that persists despite appropriate management
of KD.
A study revealed some factors which predict refractory KD:
male gender, cervical lymphadenopathy, decreased platelet
count, changes of extremities, increased total bilirubin, in-
